Among pharmaceutical preparations, orally-administered preparations are the most frequently used dosage forms. In recent years, in the light of improvement of QOL, many orally-administered preparations whose beneficial effects can be sustained by one or two doses a day have been developed. Although there are some preparations capable of sustaining their beneficial effects by one or two doses a day due to the properties of biologically active substances themselves contained in the preparations, many attempts to prolong the beneficial effects of pharmaceutical preparations by devising in production of the preparations has been made. For orally-administered sustained-release preparations, various systems including controlled release induced by controlling the diffusion of a biologically active substance using a controlled-release film or matrix, controlled release of a biologically active substance induced by erosion of a base material, controlled release of a pH-dependent biologically active substance, and time-limited controlled release for releasing a biologically active substance after a given lag time have been developed and applied. Since such an orally-administered sustained-release preparations moves through the digestive tract while it releases a biologically active substance after being administered, variation in the speed moving through the digestive tract influences production of the beneficial effect of the preparation, and the influence is different depending on the dosage form of the preparation. It has been known that a granule or fine granule that is used in multiple units is generally less influenced by the moving speed through the digestive tract than a tablet that is used in a single unit.
Since a conventional granule or fine granule preparation containing a biologically active substance often had variation in the dissolution profile (variation of dissolution) between preparations or lots, it was difficult to stably obtain a granule or fine granule preparation having a desirable dissolution profile required for producing a desirable effect. Therefore, in order to suppress variation in the dissolution profile, a granule or fine granule preparation was forced to be produced under a very narrow range of production conditions.
Various methods for producing granules are known. As one of them, Patent Document 1 discloses a method for producing a dry-coated powder having substantially a particle diameter of 500 μm or less and having a controlled dissolution property wherein a fine granular core is coated with at least one biologically active substance in combination with a water-soluble polymer.
The present inventors studied methods for producing granules having a stable dissolution profile, and as a result, found that the present invention can remarkably reduce variation in dissolution profiles between preparations or lots to provide granules stably having a desired dissolution profile. Finally the present invention was completed. That is, the present invention relates to a method for improving variation in the dissolution of a biologically active substance from granules containing the biologically active substance, which comprises heating the temperature of the granules to about 50° C. or higher and then maintaining the granules at the said temperature for about 1 minute or longer in a process for producing the granules. The present invention also relates to a method for producing granules containing a biologically active substance wherein the above-mentioned improving method is utilized.
The phrase “improving variation in the dissolution” as used herein means reducing variation in the dissolution profile (change in the dissolution rate of a biologically active substance from a pharmaceutical preparation with time). The phrase “maintaining the granules at the said temperature for about 1 minute or longer” as used herein means that the total time for maintaining the granules at the said temperature is 1 minute or longer, and continuous maintenance for 1 minute or longer and intermittent maintenance for a total time of 1 minute or longer are included. The dissolution rate means a proportion (percentage) of the dissolved amount of a biologically active substance to the amount (content) of the biologically active substance contained in a pharmaceutical preparation.
Patent Document 1: JP-A 5-92918